Novel piperidine derivatives as modulators of chemokine receptors

ABSTRACT

The invention provides a compound of formula (I): wherein R 1 , R 2 , R 3 , R 3a , R 4 , R 4a , R 5 , and R 6  are as defined; or a pharmaceutically acceptable salt thereof or a solvate thereof; compositions containing these compounds, processes for preparing them and their use as modulators of chemokine activity (especially CCR5 activity).

[0001] The present invention relates to heterocyclic derivatives havingpharmaceutical activity, to processes for preparing such derivatives, topharmaceutical compositions comprising such derivatives and to the useof such derivatives as active therapeutic agents.

[0002] Pharmaceutically active piperidine derivatives are disclosed inEP-A1-1013276, WO00/08013, WO99/38514 and WO99/04794.

[0003] Chemokines are chemotactic cytokines that are released by a widevariety of cells to attract macrophages, T cells, eosinophils, basophilsand neutrophils to sites of inflammation and also play a rôle in thematuration of cells of the immune system. Chemokines play an importantrole in immune and inflammatory responses in various diseases anddisorders, including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Thesesmall, secreted molecules are a growing superfamily of 8-14 kDa proteinscharacterised by a conserved four cysteine motif. The chemokinesuperfamily can be divided into two main groups exhibitingcharacteristic structural motifs, the Cys-X-Cys (C-X-C, or α) andCys-Cys (C-C, or β) families. These are distinguished on the basis of asingle amino acid insertion between the NH-proximal pair of cysteineresidues and sequence similarity.

[0004] The C-X-C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

[0005] The C-C chemokines include potent chemoattractants of monocytesand lymphocytes but not neutrophils such as human monocyte chemotacticproteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation,Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

[0006] Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. Thesereceptors represent good targets for drug development since agents thatmodulate these receptors would be useful in the treatment of disordersand diseases such as those mentioned above.

[0007] The CCR5 receptor is expressed on T-lymphocytes, monocytes,macrophages, dendritic cells, microglia and other cell types. Thesedetect and respond to several chemokines, principally “regulated onactivation normal T-cell expressed and secreted” (RANTES), macrophageinflammatory proteins (MIP) MIP-1a and MIP-1b and monocytechemoattractant protein-2 (MCP-2).

[0008] This results in the recruitment of cells of the immune system tosites of disease. In many diseases it is the cells expressing CCR5 thatcontribute, directly or indirectly, to tissue damage. Consequently,inhibiting the recruitment of these cells is beneficial in a wide rangeof diseases.

[0009] CCR5 is also a co-receptor for HIV-1 and other viruses, allowingthese viruses to enter cells. Blocking the receptor with a CCR5antagonist or inducing receptor intemalisation with a CCR5 agonistprotects cells from viral infection.

[0010] The present invention provides a compound of formula (I):

[0011] wherein:

[0012] R¹ is C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, heterocyclyl (itselfoptionally substituted by C₁₋₄ alkyl), C₁₋₈ alkyl (optionallysubstituted by C₃₋₆ cycloalkyl, C₅₋₆ cycloalkenyl, phenyl, heteroaryl,S(O)_(p)R⁷, CO₂R⁸), C₃₋₆ alkenyl (optionally substituted by phenyl,heteroaryl, S(O)_(q)R⁹, CO₂R¹⁰) or C₃₋₈ alkynyl;

[0013] R² is phenyl, heteroaryl, phenyl(C₁₋₄ alkyl) or heteroaryl(C₁₋₄alkyl);

[0014] R³, R^(3a), R⁴ and R^(4a) are, independently, hydrogen or C₁₋₄alkyl;

[0015] R⁵ is hydrogen, C₁₋₄ alkyl (optionally substituted by halogen,hydroxy, C₁₋₄ alkoxy, C₃₋₇ cycloalkyl, SH, C₁₋₄ alkylthio, cyano orS(O)_(q)(C₁₋₄ alkyl)), C₃₋₄ alkenyl, C₃₋₄ alkynyl or C₃₋₇ cycloalkyl;

[0016] R⁶ is phenyl, heteroaryl, phenylNH, heteroarylNH,phenyl(C₁₋₂)alkyl, heteroaryl(C₁₋₂)alkyl, phenyl(C₁₋₂ alkyl)NH orheteroaryl(C₁₋₂ alkyl)NH;

[0017] R⁷ and R⁹ are, independently, C₁₋₄ alkyl, or, when p or q is 0,C₁₋₄ acyl;

[0018] R⁸ and R¹⁰ are, independently, hydrogen or C₁₋₄ alkyl;

[0019] wherein the phenyl and heteroaryl rings of any of the foregoingare independently optionally substituted by halo, cyano, nitro, hydroxy,C₁₋₄ alkyl, C₁₋₄ alkoxy, S(O)_(m)C₁₋₄ alkyl, S(O)₂NR¹¹R¹², NHS(O)₂(C₁₋₄alkyl), NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, NHC(O)NH₂, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), C(O)(C₁₋₄alkyl), CF₃, CHF₂, CH₂F, CH₂CF₃ or OCF₃;

[0020] R¹¹ and R¹² are, independently, hydrogen or C₁₋₄ alkyl, ortogether with a nitrogen or oxygen atom, may join to form a 5- or6-membered ring which is optionally substituted with C₁₋₄ alkyl, C(O)Hor C(O)(C₁₋₄ alkyl);

[0021] m, p and q are, independently, 0, 1 or 2;

[0022] or a pharmaceutically acceptable salt thereof or a solvatethereof.

[0023] Certain compounds of the present invention can exist in differentisomeric forms (such as enantiomers, diastereomers, geometric isomers ortautomers). The present invention covers all such isomers and mixturesthereof in all proportions.

[0024] Suitable salts include acid addition salts such as ahydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate,tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.

[0025] The compounds of the invention may exist as solvates (such ashydrates) and the present invention covers all such solvates.

[0026] Alkyl groups and moieties are straight or branched chain and are,for example, methyl, ethyl, n-propyl or iso-propyl.

[0027] Alkenyl and alkynyl groups and moieties are, for example, vinyl,allyl or propargyl.

[0028] Cycloalkyl is a mono-, bi- or tri-cyclic structure such as, forexample, cyclopropyl, cyclopentyl, cyclohexyl or adamantyl.

[0029] Cycloalkenyl comprises 1 double bond and is, for example,cyclopentenyl or cyclohexenyl.

[0030] Acyl is, for example, carbonyl substituted by C₁₋₆ alkyl oroptionally substituted phenyl.

[0031] Heterocyclyl is a non-aromatic 3, 4, 5 or 6 membered ringcomprising at least one heteroatom selected from the group comprisingnitrogen, oxygen and sulphur. Heterocyclyl is, for example, aziridinyl,azetidinyl, oxetanyl, piperidinyl, 4,5-dihydro-oxazolyl,4,5-dihydroimidazolyl, morpholinyl, pyrrolidinyl, piperazinyl,tetrahydrofuryl, tetrahydropyranyl or tetrahydrothiopyranyl (wherein thesulphur is optionally substituted with 1 or 2 oxygen atoms).

[0032] Heteroaryl is an aromatic 5 or 6 membered ring comprising atleast one heteroatom selected from the group comprising nitrogen, oxygenand sulphur. Heteroaryl is, for example, pyrrolyl, imidazolyl,pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, quinolinyl,isoquinolinyl, dihydroisoquinolinyl, quinazolinyl, quinoxalinyl,indolyl, isoindolyl, benzimidazolyl, benzo[b]furyl, benzo[b]thienyl,phthalazinyl, indanyl, benzthiazolyl or cinnolinyl.

[0033] Phenylalkyl is, for example, benzyl, 1-(phenyl)ethyl or2-(phenyl)ethyl.

[0034] Heteroarylalkyl is, for example, pyridinylmethyl,pyrimidinylmethyl or 2-(pyridinyl)ethyl.

[0035] The group S(O)₂NR¹¹R¹² is, for example, S(O)₂NH₂, S(O)₂NH(C₁₋₄alkyl, S(O)₂N(C₁₋₄ alkyl)₂, S(O)₂(4-C(O)H-piperazin-1-yl) orS(O)₂(4-C(O)CH₃-piperazin-1-yl).

[0036] Phenyl(C₁₋₂ alkyl)NH is, for example, benzylamino.Heteroaryl(C₁₋₂ alkyl)NH is, for example, pyridinylCH₂NH,pyrimidinylCH₂NH or pyridinylCH(CH₃)NH.

[0037] In one particular aspect R¹ is C₃₋₇ cycloalkyl. In another aspectR¹ is cyclopropyl or cyclobutyl.

[0038] In a further aspect R² is optionally substituted phenyl(especially optionally substituted by halo, cyano, methyl, ethyl,methoxy, ethoxy, NH₂, NHCH₃, N(CH₃)₂, CF₃, CHF₂, CH₂F, CH₂CF₃ or OCF₃).In another aspect R² is optionally substituted phenyl (especiallyoptionally substituted by halogen or CF₃). Halogen is especiallychlorine or fluorine. It is especially preferred that phenyl is ortho-or meta-substituted. For example R² is unsubstituted phenyl,3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl or 4-CF₃-phenyl.

[0039] In a still further aspect R³ and R^(3a) are both hydrogen.

[0040] In yet another aspect R⁴ and R^(4a) are hydrogen or methyl.

[0041] In another aspect R⁴ is hydrogen or methyl and R^(4a) ishydrogen.

[0042] In a further aspect R⁴ and R^(4a) are hydrogen or methyl, and R³and R^(3a) are all hydrogen.

[0043] In a still further aspect R³, R^(3a), R⁴ and R^(4a) are allhydrogen.

[0044] In another aspect R⁵ is hydrogen or C₁₋₄ alkyl (such as methyl,ethyl or iso-propyl), C₃₋₄ alkenyl (for example allyl), C₃₋₄ alkynyl(for example propargyl), C₃₋₇ cycloalkyl (for example cyclopropyl) orC₃₋₇ cycloalkyl(C₁₋₄ alkyl) (for example cyclopropylCH₂).

[0045] In yet another aspect of the invention R⁵ is methyl, ethyl, allylor cyclopropyl.

[0046] In a still further aspect R⁶ is preferably optionally substitutedbenzyl, especially benzyl singly substituted (such as in the 4-position)by S(O)₂(C₁₋₄)alkyl (such as S(O)₂CH₃) or S(O)₂NR⁹R¹⁰ {R⁹ and R¹⁰ are,independently, hydrogen or C₁₋₄ alkyl, or together with a nitrogen oroxygen atom, may join to form a 5- or 6-membered ring which isoptionally substituted with C₁₋₄ alkyl, C(O)H or C(O)(C₁₋₄ alkyl)} (suchas S(O)₂NH₂, S(O)₂NH(CH₃), S(O)₂N(CH₃)₂, S(O)₂(4-C(O)H-piperazin-1-yl)or S(O)₂(4-C(O)CH₃-piperazin-1-yl). The variables R⁹ and R¹⁰ areespecially hydrogen.

[0047] In yet another aspect R⁶ is optionally substituted benzyl,especially benzyl singly substituted (such as in the 4-position) by halo(such as fluoro), S(O)₂(C₁₋₄)alkyl (such as S(O)₂CH₃) or S(O)₂NH₂.

[0048] In a further aspect R⁶ is optionally substituted benzyl,especially benzyl singly substituted (such as in the 4-position) by halo(such as fluoro) or S(O)₂(C₁₋₄)alkyl (such as S(O)₂CH₃).

[0049] In one aspect the present invention provides a compound offormula (Ia):

[0050] wherein R¹, R⁵ and R⁶ are as hereinbefore defined.

[0051] The following compounds illustrate the invention. TABLE I Allcompounds in Table I are of formula (Ia) below. (Ia)

Com- pound LCMS No. R¹ R⁵ R⁶ (MH+) 1 Cyclobutyl Me CH₂Ph-4-F 452 2Cyclobutyl Et CH₂Ph-4-F 466 3 Cyclopropyl Me CH₂Ph-4-F 438 4CH₂-2-Thiophene Et CH₂Ph-4-S(O)₂Me 568 5 C(═CH₂)CH₂CO₂Me EtCH₂Ph-4-S(O)₂Me 570 6 CH(Me)CH₂SAc—(R) Et CH₂Ph-4-S(O)₂Me 588 7CH₂S(O)₂Me Et CH₂Ph-4-S(O)₂Me 562 (M − H)+ 8 Cyclopropyl Et CH₂Ph-4-F 9Cyclobutyl Et CH₂Ph-4-S(O)₂Me 10 Cyclopropyl Et CH₂Ph-4-S(O)₂Me 11Cyclobutyl Et CH₂Ph-4-S(O)₂NH₂ 12 Cyclopropyl Et CH₂Ph-4-S(O)₂NH₂ 13Cyclobutyl allyl CH₂Ph-4-S(O)₂Me 14 Cyclopropyl allyl CH₂Ph-4-S(O)₂Me 15Cyclobutyl allyl CH₂Ph-4-S(O)₂NH₂ 16 Cyclopropyl allyl CH₂Ph-4-S(O)₂NH₂17 Cyclobutyl Cyclo- CH₂Ph-4-S(O)₂Me propyl 18 Cyclopropyl Cyclo-CH₂Ph-4-S(O)₂Me propyl 19 Cyclobutyl Cyclo- CH₂Ph-4-S(O)₂NH₂ propyl 20Cyclopropyl Cyclo- CH₂Ph-4-S(O)₂NH₂ propyl

[0052] The compounds of formula (I) and (Ia) can be prepared as shown inSchemes 1 and 2 below.

[0053] A compound of formula (I) or (Ia) can be prepared by reacting acompound of formula (II):

[0054] with either an acid halide of formula R¹C(O)Cl in a suitablesolvent (such as a chlorinated solvent, for example CH₂Cl₂), or an acidof formula R¹CO₂H in the presence of a suitable coupling agent and in asuitable solvent. Suitable coupling agents include PyBrOP™(bromo-tris-pyrrolidino-phosphonium hexafluorophosphate), HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), HBTU(O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate),EDCI (ethyl dimethylaminopropyl carbodiimide hydrochloride), HOBT(1-hydroxybenzotriazole), and DMAP (N,N-dimethylaminopyridine).

[0055] In a further aspect the invention provides processes forpreparing the compounds of formula (I) or (Ia). Many of theintermediates in the processes shown in Schemes 1 and 2 are novel andthese are provided as further features of the invention.

[0056] The compounds of the invention have activity as pharmaceuticals,in particular as modulators (such as agonists, partial agonists, inverseagonists or antagonists) of chemokine receptor (especially CCR5)activity, and may be used in the treatment of autoimmune, inflammatory,proliferative or hyperproliferative diseases, orimmunologically-mediated diseases (including rejection of transplantedorgans or tissues and Acquired Immunodeficiency Syndrome (AIDS)).Examples of these conditions are:

[0057] (1) (the respiratory tract) obstructive diseases of airwaysincluding: chronic obstructive pulmonary disease (COPD) (such asirreversible COPD); pulmonary fibrosis; asthma {such as bronchial,allergic, intrinsic, extrinsic or dust asthma, particularly chronic orinveterate asthma (for example late asthma or airwayshyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis};acute, allergic, atrophic rhinitis or chronic rhinitis includingrhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitissicca or rhinitis medicamentosa; membranous rhinitis including croupous,fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonalrhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis;sarcoidosis; farmer's lung and related diseases; nasal polyposis;fibroid lung or idiopathic interstitial pneumonia;

[0058] (2) (bone and joints) arthrides including rheumatic, infectious,autoimmune, seronegative spondyloarthropathies (such as ankylosingspondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease,Sjogren's syndrome or systemic sclerosis;

[0059] (3) (skin and eyes) psoriasis, atopic dermatitis, contactdermatitis or other eczmatous dermitides, seborrhoetic dermatitis,lichen planus, phemphigus, bullous phemphigus, epidermolysis bullosa,urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias,uveitis, alopecia areata or vernal conjunctivitis;

[0060] (4) (gastrointestinal tract) Coeliac disease, proctitis,eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerativecolitis, irritable bowel disease or food-related allergies which haveeffects remote from the gut (for example migraine, rhinitis or eczema);

[0061] (5) (Allograft rejection) acute and chronic following, forexample, transplantation of kidney, heart, liver, lung, bone marrow,skin or cornea; or chronic graft versus host disease; and/or

[0062] (6) (other tissues or diseases) Alzheimer's disease, multiplesclerosis, atherosclerosis, inhibiting the entry of viruses into targetcells, Acquired Immunodeficiency Syndrome (AIDS), lupus disorders (suchas lupus erythematosus or systemic lupus), erythematosus, Hashimoto'sthyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome,eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatousleprosy), peridontal disease, sezary syndrome, idiopathicthrombocytopenia pupura, disorders of the menstrual cycle,glomerulonephritis or cerebral malaria.

[0063] The compounds of the present invention are also of value ininhibiting the entry of viruses (such as human immunodeficiency virus(HIV)) into target calls and, therefore, are of value in the preventionof infection by viruses (such as HIV), the treatment of infection byviruses (such as HIV) and the prevention and/or treatment of acquiredimmune deficiency syndrome (ADS).

[0064] According to a further feature of the invention there is provideda compound of the formula (I) or (Ia), or a pharmaceutically acceptablesalt thereof or a solvate thereof, for use in a method of treatment of awarm blooded animal (such as man) by therapy (including prophylaxis).

[0065] According to a further feature of the present invention there isprovided a method for modulating chemokine receptor activity (especiallyCCR5 receptor activity) in a warm blooded animal, such as man, in needof such treatment, which comprises administering to said animal aneffective amount of a compound of the present invention, or apharmaceutically acceptable salt thereof or a solvate thereof.

[0066] The present invention further provides a method of treating achemokine mediated disease state (especially a CCR5 mediated diseasestate, such as rheumatoid arthritis) in a warm blooded animal (such asman) suffering from, or at risk of, said disease, which comprisesadministering to an animal in need of such treatment a therapeuticallyeffective amount of a compound of formula (I) or (Ia), or apharmaceutically acceptable salt thereof or solvate thereof.

[0067] The present invention also provides the use of a compound of theinvention, or a pharmaceutically acceptable salt thereof or a solvatethereof, as a medicament, especially a medicament for the treatment oftransplant rejection, respiratory disease, psoriasis or arthritis(especially rheumatoid arthritis). [Respiratory disease is, for example,COPD, asthma {such as bronchial, allergic, intrinsic, extrinsic or dustasthma, particularly chronic or inveterate asthma (for example lateasthma or airways hyper-responsiveness)} or rhinitis {acute, allergic,atrophic rhinitis or chronic rhinitis including rhinitis caseosa,hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitismedicamentosa; membranous rhinitis including croupous, fibrinous orpseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitisincluding rhinitis nervosa (hay fever) or vasomotor rhinitis}; and isparticularly asthma or rhinitis].

[0068] The invention also provides a compound of the formula (I) or(Ia), or a pharmaceutically acceptable salt thereof or a solvatethereof, for use as a medicament, especially a medicament for thetreatment of transplant rejection, respiratory disease, psoriasis orarthritis (especially rheumatoid arthritis).

[0069] The invention also provides a compound of the formula (I) or(Ia), or a pharmaceutically acceptable salt thereof or a solvatethereof, for use in therapy (including prophylaxis); for example in thetreatment of a chemokine mediated disease state (especially a CCR5mediated disease state) in a warm blooded animal, such as man, such asin the treatment of rheumatoid arthritis.

[0070] The invention also provides a compound of the formula (I) or(Ia), or a pharmaceutically acceptable salt thereof or a solvatethereof, for use as a medicament, especially a medicament for thetreatment of rheumatoid arthritis.

[0071] In another aspect the present invention provides the use of acompound of the formula (I) or (Ia), or a pharmaceutically acceptablesalt thereof or a solvate thereof, in the manufacture of a medicamentfor use in therapy (for example in modulating chemokine receptoractivity (especially CCR5 receptor activity (especially in the treatmentof rheumatoid arthritis)) in a warm blooded animal, such as man).

[0072] The invention further provides the use of a compound of formula(I) or (Ia), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of:

[0073] (1) (the respiratory tract) obstructive diseases of airwaysincluding: chronic obstructive pulmonary disease (COPD) (such asirreversible COPD); asthma {such as bronchial, allergic, intrinsic,extrinsic or dust asthma, particularly chronic or inveterate asthma (forexample late asthma or airways hyper-responsiveness)}; bronchitis {suchas eosinophilic bronchitis}; acute, allergic, atrophic rhinitis orchronic rhinitis including rhinitis caseosa, hypertrophic rhinitis,rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranousrhinitis including croupous, fibrinous or pseudomembranous rhinitis orscrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hayfever) or vasomotor rhinitis; sarcoidosis; farmer's lung and relateddiseases; nasal polyposis; fibroid lung or idiopathic interstitialpneumonia;

[0074] (2) (bone and joints) arthrides including rheumatic, infectious,autoimmune, seronegative spondyloarthropathies (such as ankylosingspondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease,Sjogren's syndrome or systemic sclerosis;

[0075] (3) (skin and eyes) psoriasis, atopic dermatitis, contactdermatitis or other eczmatous dermitides, seborrhoetic dermatitis,lichen planus, phemphigus, bullous phemphigus, epidermolysis bullosa,urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias,uveitis, alopecia areata or vernal conjunctivitis;

[0076] (4) (gastrointestinal tract) Coeliac disease, proctitis,eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerativecolitis, irritable bowel disease or food-related allergies which haveeffects remote from the gut (for example migraine, rhinitis or eczema);

[0077] (5) (Allograft rejection) acute and chronic following, forexample, transplantation of kidney, heart, liver, lung, bone marrow,skin or cornea; or chronic graft versus host disease; and/or

[0078] (6) (other tissues or diseases) Alzheimer's disease, multiplesclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS),lupus disorders (such as lupus erythematosus or systemic lupus),erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type Idiabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome,leprosy (such as lepromatous leprosy), peridontal disease, sezarysyndrome, idiopathic thrombocytopenia pupura or disorders of themenstrual cycle;

[0079] in a warm blooded animal, such as man.

[0080] In order to use a compound of the invention, or apharmaceutically acceptable salt thereof or solvate thereof, for thetherapeutic treatment of a warm blooded animal, such as man, inparticular modulating chemokine receptor (for example CCR5 receptor)activity, said ingredient is normally formulated in accordance withstandard pharmaceutical practice as a pharmaceutical composition.

[0081] Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula (I)or (Ia), or a pharmaceutically acceptable salt thereof or a solvatethereof (active ingredient), and a pharmaceutically acceptable adjuvant,diluent or carrier. In a further aspect the present invention provides aprocess for the preparation of said composition which comprises mixingactive ingredient with a pharmaceutically acceptable adjuvant, diluentor carrier. Depending on the mode of administration, the pharmaceuticalcomposition will preferably comprise from 0.05 to 99% w (per cent byweight), more preferably from 0.05 to 80% w, still more preferably from0.10 to 70% w, and even more preferably from 0.10 to 50% w, of activeingredient, all percentages by weight being based on total composition.

[0082] The pharmaceutical compositions of this invention may beadministered in standard manner for the disease condition that it isdesired to treat, for example by topical (such as to the lung and/orairways or to the skin), oral, rectal or parenteral administration. Forthese purposes the compounds of this invention may be formulated bymeans known in the art into the form of, for example, aerosols, drypowder formulations, tablets, capsules, syrups, powders, granules,aqueous or oily solutions or suspensions, (lipid) emulsions, dispersiblepowders, suppositories, ointments, creams, drops and sterile injectableaqueous or oily solutions or suspensions.

[0083] A suitable pharmaceutical composition of this invention is onesuitable for oral administration in unit dosage form, for example atablet or capsule which contains between 0.1 mg and 1 g of activeingredient.

[0084] In another aspect a pharmaceutical composition of the inventionis one suitable for intravenous, subcutaneous or intramuscularinjection.

[0085] Each patient may receive, for example, an intravenous,subcutaneous or intramuscular dose of 0.01 mgkg⁻¹ to 100 mgkg⁻¹ of thecompound, preferably in the range of 0.1 mgkg⁻¹ to 20 mgkg⁻¹ of thisinvention, the composition being administered 1 to 4 times per day. Theintravenous, subcutaneous and intramuscular dose may be given by meansof a bolus injection. Alternatively the intravenous dose may be given bycontinuous infusion over a period of time. Alternatively each patientwill receive a daily oral dose which is approximately equivalent to thedaily parenteral dose, the composition being administered 1 to 4 timesper day.

[0086] The following illustrate representative pharmaceutical dosageforms containing the compound of formula (I) or (Ia), or apharmaceutically acceptable salt thereof or a solvent thereof (hereafterCompound X), for therapeutic or prophylactic use in humans:

[0087] (a) Tablet I mg/tablet Compound X 100 Lactose Ph. Eur. 179Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0

[0088] (b) Tablet II mg/tablet Compound X 50 Lactose Ph. Eur. 229Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0

[0089] (c) Tablet III mg/tablet Compound X 1.0 Lactose Ph. Eur. 92Croscarmellose sodium 4.0 Polyvinylpyrrolidone 2.0 Magnesium stearate1.0

[0090] (d) Capsule mg/capsule Compound X 10 Lactose Ph. Eur. 389Croscarmellose sodium 100 Magnesium stearate 1.0

[0091] (e) Injection I (50 mg/ml) Compound X 5.0% w/v Isotonic aqueoussolution to 100%

[0092] Buffers, pharmaceutically-acceptable cosolvents such aspolyethylene glycol, polypropylene glycol, glycerol or ethanol orcomplexing agents such as hydroxy-propyl β-cyclodextrin may be used toaid formulation.

[0093] The above formulations may be obtained by conventional procedureswell known in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

[0094] The invention will now be illustrated by the followingnon-limiting examples in which, unless stated otherwise:

[0095] (i) temperatures are given in degrees Celsius (° C.); operationswere carried out at room or ambient temperature, that is, at atemperature in the range of 18-25° C.;

[0096] (ii) organic solutions were dried over anhydrous magnesiumsulphate; evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) witha bath temperature of up to 60° C.;

[0097] (iii) chromatography unless otherwise stated means flashchromatography on silica gel; thin layer chromatography (TLC) wascarried out on silica gel plates; where a “Bond Elut” column is referredto, this means a column containing 10 g or 20 g of silica of 40 micronparticle size, the silica being contained in a 60 ml disposable syringeand supported by a porous disc, obtained from Varian, Harbor City,Calif., USA under the name “Mega Bond Elut SI”. Where an “Isolute™ SCXcolumn” is referred to, this means a column containing benzenesulphonicacid (non-endcapped) obtained from International Sorbent TechnologyLtd., 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, MidClamorgan, UK. Where “Argonaut™ PS-tris-amine scavenger resin” isreferred to, this means a tris-(2-aminoethyl)amine polystyrene resinobtained from Argonaut Technologies Inc., 887 Industrial Road, Suite G,San Carlos, Calif., USA.

[0098] (iv) in general, the course of reactions was followed by TLC andreaction times are given for illustration only;

[0099] (v) yields, when given, are for illustration only and are notnecessarily those which can be obtained by diligent process development;preparations were repeated if more material was required;

[0100] (vi) when given, ¹H NMR data is quoted and is in the form ofdelta values for major diagnostic protons, given in parts per million(ppm) relative to tetramethylsilane (TMS) as an internal standard,determined at 300 MHz using perdeuterio DMSO (CD₃SOCD₃) as the solventunless otherwise stated; coupling constants (J) are given in Hz;

[0101] (vii) chemical symbols have their usual meanings; SI units andsymbols are used;

[0102] (viii) solvent ratios are given in percentage by volume;

[0103] (ix) mass spectra (MS) were run with an electron energy of 70electron volts in the chemical ionisation (APCI) mode using a directexposure probe; where indicated ionisation was effected by electrospray(ES); where values for m/z are given, generally only ions which indicatethe parent mass are reported, and unless otherwise stated the mass ionquoted is the positive mass ion-(M+H)⁺;

[0104] (x) LCMS characterisation was performed using a pair of Gilson306 pumps with Gilson 233 XL sampler and Waters ZMD4000 massspectrometer. The LC comprised water symmetry 4.6×50 column C18 with 5micron particle size. The eluents were: A, water with 0.05% formic acidand B, acetonitrile with 0.05% formic acid. The eluent gradient wentfrom 95% A to 95% B in 6 minutes. Where indicated ionisation waseffected by electrospray (ES); where values for m/z are given, generallyonly ions which indicate the parent mass are reported, and unlessotherwise stated the mass ion quoted is the positive mass ion-(M+H)⁺ and

[0105] (xi) the following abbreviations are used: DMFN,N-dimethylformamide; THF tetrahydrofuran; DCM dichloromethane; HATUO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; Boc tert-butoxycarbonyl; and MeOH methanol.

EXAMPLE 1

[0106] This Example illustrates the preparation ofN-[1-(N-phenyl-N-cyclobutanecarbonyl-2-ethylamino)-4-piperidinyl]-N-methyl-4-fluorophenylacetamide(Compound No. 1 of Table I).

[0107] To a solution of cyclobutane carboxylic acid (50 mg, 0.5 mmol) indichloromethane (DCM) (10 mL) was added oxalyl chloride (64 mg, 0.5mmol) and the resulting mixture was stirred at room temperature for 5 h.The mixture was evaporated and the residue was dissolved in DCM (10 mL).N-[1-(N-Phenyl-2-ethylamino)-4-piperidinyl]-N-methyl-4-fluorophenylacetamide(150 mg, 0.43 mmol) was added followed by N,N-diisopropylethylamine (1.5mmol). The resulting mixture was stirred at room temperature for 20 h,then partitioned between water and ethyl acetate. The organic phase wasdried and evaporated. The crude product was purified by eluting througha 20 g Bond Elut cartridge with a gradient of 0-30% methanol in ethylacetate yielding the title compound (67 mg); ¹H NMR: δ1.23 (br d, 1H),1.36 (br d, 1H), 1.6 (m, 4H), 1.92 (m, 2H), 2.05 (m, 3H), 2.30 (m, 2H),2.61 (s, 1H), 2.80 (s, 3H), 2.9-3.8 (m, 7H), 4.20 (m, 1H), 7.05 (m, 3H),7.20 (d, 3H), 7.38 (m, 3H); MS:452.

[0108] Compound No. 3 of Table I was prepared in a similar manner:

[0109]¹H NMR: δ0.61 (m, 2H), 0.76 (m, 2H), 1.30 (br dd, 2H), 1.50 (m,2H), 1.90 (br q, 2H), 2.30 (br s, 2H), 2.60 (s, 1H), 2.80 (s, 3H),3.2-3.8 (m, 6H), 4.18 (m 1H), 7.05 (m 3H), 7.20 (m 2H), 7.32 (d, 2H),7.40 (m, 2H).

[0110] Methods

[0111] Starting materials are commercially available, have beendescribed in the literature or can be prepared by adaptation ofliterature methods. Examples of literature methods include: P. Richter,Ch. Garbe and G. Wagner, E. Ger. Pharmazie, 1974, 29(4), 256-262; C.Oniscu, D. Nicoara and G. Funieru, “4-(Ureidosulfonyl)phenylacetic acidand its ureide”, R079-966646, (Romanian document); and M. A. Zahran, M.M. Ali, Y. A. Mohammed and A. A. Shehata, Int. J. Chem., 1993, 4(3), 61.

[0112] To a solution of1-(N-phenyl-2-ethylamino)-4-methylaminopiperidine (466 mg, 2.0 mmol) inN,N-dimethylformamide (DMF) (10 mL) was added 4-fluorophenylacetic acid(323 mg, 2.1 mmol), HATU (800 mg, 2.1 mmol) andN,N-diisopropylethylamine (0.4 mL) and the resulting mixture was stirredat room temperature for 20 h. Water was added and the resulting mixtureextracted with ethyl acetate. The organic extract was dried andevaporated affording the title compound (340 mg); ¹H NMR: 1.40 (m, 2H),1.70 (m, 2H), 2.65 (m, 2H), 2.80 (s, 3H), 2.9-3.2 (m, 5H), 3.70 (m, 3H),4.23 (m 1H), 6.55 (m, 3H), 7.02 (m, 4H), 7.20 (m, 2H); MS: 370.

[0113] To a solution of 1-(2-anilinoacetyl)-4-Boc-aminopiperidine (3.33g, 10.0 mmol) in THF (100 mL) was added lithium aluminium hydride (20 mL1M in THF) and the resulting mixture stirred at reflux for 16 h. Aftercooling to room temperature the reaction was treated with 2M aqueoussodium hydroxide solution and the resulting mixture was filtered. Thefiltrate was evaporated then redissolved in ethyl acetate. This solutionwas washed with water, dried and evaporated giving the title compound asan oil (2.1 g); ¹H NMR: 1.21 (dq, 2H), 1.75 (br d, 2H), 1.97 (dt, 2H0,2.26 (m, 4H), 2.45 (t, 2H), 2.81 (br d, 2H), 3.07 (q, 2H), 5.27 (t, 1H),6.49 (t, 1H), 6.55 (d, 2H), 7.04 (t, 2H); MS: 234.

[0114] To a solution of 4-Boc-aminopiperidine (7.0 g, 35 mmol) in (DMF)(100 mL) was added 2-anilinoacetic acid (4.89 g, 33 mmol), HATU (13.3 g,35 mmol) and N,N-diisopropylethylamine (6.1 mL) and the resultingmixture was stirred at room temperature for 20 h. Water was added andthe resulting precipitate collected and dried affording the titlecompound as a solid (8.2 g, 74%); ¹H NMR: 1.39 (s, 9H), 1.76 (br t, 2H),2.75 (m, 1H), 3.04 (m, 1H), 3.5 (m, 3H), 3.84 (m, 3H), 4.20 (br d, 1H),5.42 (t, 1H), 6.55 (t, 1H), 6.60 (d, 2H), 6.85 (m, 1H), 7.05 (t, 2H);MS: 278 (MH⁺-2-butene).

[0115] To a mixture ofN-(4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (2.0 g, 6.2mmol) and N-(2-chloroethyl)aniline hydrochloride (1.2 g, 6.2 mmol) (J.Med. Chem. 1965, 173) in 4-methyl-2-pentanone (15 mL) was addedpotassium carbonate (2.56 g, 18.6 mmol) and potassium iodide (150 mg,0.9 mmol) and the resulting mixture stirred at reflux for 20 h. Aftercooling to room temperature the solid was removed by filtration and thefiltrate concentrated. The residue was purified by Bond Elutchromatography (eluent 5% MeOH/DCM) to afford, after trituration withdiethyl ether, the title compound as a white solid (1.30 g, 50%); ¹H NMR(d6 DMSO, 373K): 1.1 (t, 3H), 1.4 (m, 2H), 1.8 (m, 2H), 2.1 (m, 2H), 2.5(m, 2H), 3.1 (m, 5H), 3.3 (q, 2H), 3.8 (s, 2H), 5.0 (m, 1H), 6.6 (m,3H), 7.1 (dd, 2H), 7.5 (d, 2H), 7.8 (d, 2H); MS: 444.

[0116] To a solution ofN-(1-phenylmethyl-4-piperidinyl)-N-ethyl-4-methanesulfonylphenyl-acetamide(34 g, 82 mmol) in ethanol (600 ml) was added ammonium formate (40 g).The mixture was purged with argon and 30% Pd on carbon (4.2 g) wasadded. The resulting mixture was stirred at reflux for 4 h, then allowedto cool and filtered through diatomaceous earth. The filtrate wasevaporated to give a thick oil which solidified on standing to yield thetitle compound (24.9 g. 77 mmol); ¹H NMR: 1.02 and 1.15 (t, 3H), 1.4-1.6 (br m, 4H), 2.45 (m, 2H), 2.93 (br m, 2H), 3.18 (s, 3H), 3.20 and3.32 (q, 2H), 3.72 and 4.18 (m, 1H), 3.80 and 3.87 (s, 2H), 7.50 (m,2H), 7.85 (m, 2H); MS: 325.

[0117] To a solution of 1-phenylmethyl-4-ethylaminopiperidinedihydrochloride (32.0 g, 110 mmol) in DCM (500 mL) was addedN,N-diisopropylethylamine (60 mL) with stirring to ensure completedissolution. 4-Methanesulfonylphenylacetic acid (25.0 g, 117 mmol),4-dimethylaminopyridine (2.0 g) and dicyclohexylcarbodiimide (25.0 g,121 mmol) were added and the resulting mixture was stirred at roomtemperature for 20 h. The precipitate was removed by filtration and theresulting solution was washed successively with 2N aqueous HCl, waterand 1N aqueous NaOH, dried (MgSO₄) and evaporated. The residue waspurified by silica gel chromatography (eluent 10% MeOH/ethyl acetate) toafford the title compound (35 g, 76%); ¹H NMR: 1.00 and 1.14 (t, 3H),1.45 and 1.70 (m, 2H), 1.95 (br m, 2H), 2.80 (br m, 2H), 3.18 (s, 3H),3.20 and 3.33 (q, 2H), 3.45 (s, 2H), 3.80 and 3.87 (s, 2H), 3.70 and4.10 (m, 1H), 7.2-7.3 (m, 5H), 7.48 (m, 2H), 7.82 (m, 2H); MS: 415.

[0118] To a solution of 1-phenylmethyl-4-piperidone (25.0 g, 132 mmol)in THF (250 mL) was added ethylamine hydrochloride (12.0 g, 147 mmol)and methanol (50 mL) and the resulting mixture stirred at roomtemperature for 10 min. Sodium triacetoxyborohydride (40 g, 189 mmol)was added portionwise and the resulting mixture stirred at roomtemperature for 1 h. 2M Sodium hydroxide solution (250 mL) was added andthe resulting mixture extracted with diethyl ether. The organic extractswere dried (K₂CO₃) and evaporated to give1-phenylmethyl-4-ethylaminopiperidine as an oil. This was dissolved inethanol (500 mL) and concentrated hydrochloric acid (20 mL) was added.The resulting crystals were collected, washed with diethyl ether anddried giving the title compound as a solid (38 g); ¹H NMR (CDCl₃): 1.10(t, 3H), 1.40 (m, 2H), 1.83 (m, 2H), 2.02 (m, 2H), 2.65 (q, 2H), 2.85(m, 2H), 3.50 (s, 2H), 3.75 (m, 1H), 7.2-7.4 (m, 5H); MS: 219.

[0119] N-[1-(N-Phenyl-2-ethylamino)-4-piperidinyl]-N-ethyl-4-fluorophenylacetamide

[0120] This was prepared by reactingN-4-piperidinyl-N-ethyl-4-fluorophenylacetamide withN-(2-chloroethyl)aniline hydrochloride according to the procedure usedfor Method 4; ¹H NMR: 1.0 and 1.5 (t, 3H), 1.3 (m, 1H) 1.5 (m, 1H), 1.7(m, 2H), 2.0 (m, 2H), 2.4 (m, 2H), 2.9 (m, 2H), 3.1 (m, 2H), 3.2 (m,2H), 3.6 and 3.7 (s, 2H), 4.1 (m, 1H), 5.2 (br s, 1H), 6.5 (m, 3H), 7.0(dd, 2H), 7.1 (dd, 2H), 7.2 (m, 2H); MS: 384.

[0121] This was prepared by reactingN-(1-phenylmethyl-4-piperidinyl-N-ethyl-4-fluoro-phenylacetamideaccording to the procedure used for Method 5; ¹H NMR: (formic acidsalt): 0.97 and 1.10 (t, 3H), 1.46 and 1.62 (m, 2H), 1.8-2.0 (m, 2H),2.78 (m, 2H), 3.1-3.3 (m, 4H), 3.65 and 3.74 (s, 2H), 3.97 and 4.22 (m,1H), 7.08 (m, 2H), 7.25 (m, 2H), 8.42 (s, 1H); MS: 265.

[0122] This was prepared by reacting1-phenylmethyl-4-ethylaminopiperidine dihydrochloride with4-fluorophenylacetic acid according to the procedure used for Method 6;¹H NMR (CDCl₃): 1.13 and 1.19 (t, 3H), 1.35 and 1.85 (m, 2H), 1.74 and2.08 (m, 2H), 2.90 (br m, 2H), 3.30 (m, 2H), 3.46 (s, 2H), 3.66 (s, 2H),3.55 and 4.42 (m, 1H), 7.00 (m, 2H), 7.2-7.3 (m, 7H); MS: 355.

EXAMPLE 2

[0123] The ability of compounds to inhibit the binding of RANTES orMIP-1α was assessed by an in vitro radioligand binding assay. Membraneswere prepared from Chinese hamster ovary cells which expressed therecombinant human CCR5 receptor. These membranes were incubated with 0.1nM iodinated RANTES or MIP-1α, scintillation proximity beads and variousconcentrations of the compounds of the invention in 96-well plates. Theamount of iodinated RANTES or MIP-1α bound to the receptor wasdetermined by scintillation counting. Competition curves were obtainedfor compounds and the concentration of compound which displaced 50% ofbound iodinated RANTES or MIP-1α was calculated (IC₅₀). Certaincompounds of formula (I) had an IC₅₀ of less than 50 μM.

1. A compound of formula (I):

wherein: R¹ is C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, heterocyclyl (itselfoptionally substituted by C₁₋₄ alkyl), C₁₋₈ alkyl (optionallysubstituted by C₃₋₆ cycloalkyl, C₅₋₆ cycloalkenyl, phenyl, heteroaryl,S(O)_(p)R⁷, CO₂R⁸), C₃₋₆ alkenyl (optionally substituted by phenyl,heteroaryl, S(O)_(q)R⁹, CO₂R¹⁰) or C₃₋₈ alkynyl; R² is phenyl,heteroaryl, phenyl(C₁₋₄ alkyl) or heteroaryl(C₁₋₄ alkyl); R³, R^(3a), R⁴and R^(4a) are, independently, hydrogen or C₁₋₄ alkyl; R⁵ is hydrogen,C₁₋₄ alkyl (optionally substituted by halogen, hydroxy, C₁₋₄ alkoxy,C₃₋₇ cycloalkyl, SH, C₁₋₄ alkylthio, cyano or S(O)_(q)(C₁₋₄ alkyl)),C₃₋₄ alkenyl, C₃₋₄ alkynyl or C₃₋₇ cycloalkyl; R⁶ is phenyl, heteroaryl,phenylNH, heteroarylNH, phenyl(C₁₋₂)alkyl, heteroaryl(C₁₋₂)alkyl,phenyl(C₁₋₂ alkyl)NH or heteroaryl(C₁₋₂ alkyl)NH; R⁷ and R⁹ are,independently, C₁₋₄ alkyl, or, when p or q is 0, C₁₋₄ acyl; R⁸ and R¹⁰are, independently, hydrogen or C₁₋₄ alkyl; wherein the phenyl andheteroaryl rings of any of the foregoing are independently optionallysubstituted by halo, cyano, nitro, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy,S(O)_(m)C₁₋₄ alkyl, S(O)₂NR¹¹R¹², NHS(O)₂(C₁₋₄ alkyl), NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, NHC(O)NH₂, C(O)NH₂, C(O)NH(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃, CHF₂,CH₂F, CH₂CF₃ or OCF₃; R¹¹ and R¹² are, independently, hydrogen or C₁₋₄alkyl, or together with a nitrogen or oxygen atom, may join to form a 5-or 6-membered ring which is optionally substituted with C₁₋₄ alkyl,C(O)H or C(O)(C₁₋₄ alkyl); m, p and q are, independently, 0, 1 or 2; ora pharmaceutically acceptable salt thereof or a solvate thereof.
 2. Acompound of formula (I) as claimed in claim 1 wherein R¹ is C₃₋₇cycloalkyl.
 3. A compound of formula (I) as claimed in claim 1 or 2wherein R² is phenyl optionally substituted by halogen or CF₃.
 4. Acompound of formula (I) as claimed in claim 1, 2 or 3 wherein R³ andR^(3a) are both hydrogen.
 5. A compound of formula (I) as claimed inclaim 1, 2, 3 or 4 wherein R⁴ is hydrogen or methyl and R^(4a) ishydrogen.
 6. A compound of formula (I) as claimed in claim 1, 2, 3, 4 or5 wherein R⁵ is hydrogen, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₇ cycloalkyl orC₃₋₇ cycloalkyl(C₁₋₄ alkyl).
 7. A compound of formula (I) as claimed inclaim 1, 2, 3, 4, 5 or 6 wherein R⁶ is benzyl singly substituted byS(O)₂(C₁₋₄)alkyl or S(O)₂NR⁹R¹⁰; wherein R⁹ and R¹⁰ are, independently,hydrogen or C₁₋₄ alkyl, or together with a nitrogen or oxygen atom, jointo form a 5- or 6-membered ring which is optionally substituted withC₁₋₄ alkyl, C(O)H or C(O)(C₁₋₄ alkyl).
 8. A process for the preparationof a compound of formula (I) as claimed in claim 1, the processcomprising reacting a compound of formula (II):

with either an acid halide of formula R¹C(O)Cl in a suitable solvent, oran acid of formula R¹CO₂H in the presence of a suitable coupling agentand in a suitable solvent.
 9. A pharmaceutical composition whichcomprises a compound of the formula (I), or a pharmaceuticallyacceptable salt thereof or solvate thereof, and a pharmaceuticallyacceptable adjuvant, diluent or carrier.
 10. A compound of the formula(I), or a pharmaceutically acceptable salt thereof or solvate thereof asclaimed in claim 1 to 7, for use in therapy.
 11. A compound of formula(I), or a pharmaceutically acceptable salt thereof or solvate thereof asclaimed in claim 1 to 7, in the manufacture of a medicament for use intherapy.
 12. A method of treating a chemokine mediated disease state ina warm blooded animal suffering from, or at risk of, said disease, whichcomprises administering to an animal in need of such treatment atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof or solvate thereof as claimedin claim 1 to 7.